MR Contrast Agents. Why Use Contrast Agents in MRI? Why Use Contrast Agents in MRI? US Agents. Understanding and Embracing Change

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1 Why Use Contrast Agents in MRI? Improve disease detection and characterization Increase sensitivity to extent of disease MR Contrast Agents Understanding and Embracing Change Kristan Harrington, MBA, RT (R) (MR) (ARRT) Increase differentiation between normal and abnormal tissues Track enhancement patterns Demonstrate pathophysiology Perfusion Clearance Why Use Contrast Agents in MRI? US Agents Generic Name Gadopentetate dimeglumine Gadoteridol Gadodiamide Gadoversetamide Gadobutrol Gadoterate meglumine Gadobenate dimeglumine Gadoxetate disodium Gadofosveset trisodium Trade Name Magnevist ProHance Omniscan OptiMARK Gadavist Dotarem MultiHance Eovist Ablavar

2 Gd-Based Contrast Media Variable Properties Chelate design -Clinical Safety Mechanism of Action Ionic/Non-Ionic - Clinical Safety Excretion- Renal or Biliary Molar concentration- Volume Delivery in ml based on Dose Relaxivity- Effectiveness based on Dose Question... TR (Time of Repetition) TR T1-Relaxation T1-Relaxation Signal ( brightness ) Signal ( brightness ) TR Time TR Time

3 Water Molecule Gadolinium Agent Molecular tumbling-rate slows Signal intensity vs TR T1-relaxation time shortens Contrast 1 T1 = r1 [Gd] With contrast T1=1/(R10 + r1ct) Without contrast Relaxivity (r 1 ) is a measure of the effect on the T1-relaxation rate Courtesy Dr. E. Kanal Brain Intra-axial Extra-axial Pre Low-Grade Lesion Post

4 Intraindividual Crossover Comparison Gadopentetate vs Gadobenate: Timecourse Median increase in tumor signal intensity (normalized) Gadobenate (MultiHance) Gadopentetate (Magnevist) *p< *Lesion contrast significantly higher after MultiHance administration (N = 24) Data from Essig M. *p<.01 Time post-injection (min) Appl Radiol 2003; April (suppl): Low-Grade Lesion Take another look.. *p<.001 *p <.01 Pre Post Increasing Signal (Contrast) Reduce background (MTC) Increase dose Increase concentration (1.0 molar vs 0.5 molar) Increase Relaxivity Concentration 1.0 Molar 0.5 Molar Macrocylic Agents Dosing Dose is determined by amount of gadolinium not volume of the agent Dosing Dose is determined by amount of gadolinium not volume of the agent ProHance 0.5 molar concentration Same for: - Magnevist Standard dose: 0.1 mmol/kg - MultiHance - Omniscan Patient weight: 80 Kg (approx 180 lbs) - Optimark 80 x 0.1 = 8 8 x 2 =16 ml Standard dose: 0.1 mmol/kg Gadavist 1.0 molar concentration Patient weight: 80 Kg (approx 180 lbs) 80 x 0.1 = 8 ml

5 Increasing Relaxivity No data to support increased safety due to reduced volume but same dose Standard Benzyloxymethyl chain Gd-BOPTA Increased concentration in the bottle does not translate to increased concentration in tissues Gd +3 & H20 Weak / Transient Interaction w/proteins Protein 2-fold increase in relaxivity (r1, r2) effectivness Signal intensity vs TR Colosimo C et al: Detection of intracranial metastases. A multicenter, intrapatient comparison of gadobenate dimeglumine-enhanced MRI with routinely used contrast agents at equal dosage. Invest Radiol 36-2: 72-81, 2001 Higher Signal from the lesion = more contrast Seeing it better is seeing it better Dotarem MultiHance With MultiHance T1=1/(R10 + r1ct) Courtesy Dr. E. Kanal Without contrast Standard Gd 0.1 mmol 0.1 mmol Maravilla K et al: Contrast Enhancement of Central Nervous System Lesions: Multicenter Intraindividual Crossover Comparative Study of Two MR Contrast Agents. Radiology Volume 240: Number 2 - August 2006 Qualitative Measures Lesion Border Delineation Extent of Lesion Internal Morphology Degree of Enhancement Magnevist 0.1 MultiHance 0.1 All Readers, All Measures Courtesy Dr. Ken Maravilla Courtesy Dr. Ken Maravilla Radiology Volume 240: Number 2 - August 2006

6 Quantitative Measures Additional References (partial list) Colosimo C, et al, Comparison of gadobenate dimeglumine (Gd-BOPTA) with gadopentetate dimeglumine (Gd-DTPA) for enhanced MR imaging of brain and spine tumors in children., Pediatr Radiol May;35(5): Essig M, et al, Enhancing lesions of the brain: intraindividual crossover comparison of contrast enhancement after gadobenate dimeglumine versus established gadolinium comparators., Acad Radiol Jun;13(6): Knopp MV, Gadobenate dimeglumine-enhanced MRI of the breast: analysis of dose response and comparison with gadopentetate dimeglumine., AJR Am J Roentgenol Sep;181(3): Kuhn MJ, et al, Evaluation of intraaxial enhancing brain tumors on magnetic resonance imaging: intraindividual crossover comparison of gadobenate dimeglumine and gadopentetate dimeglumine for visualization and assessment, and implications for surgical intervention., J Neurosurg Apr;106(4): Mean % Signal Enhancement Courtesy Dr. Ken Maravilla Radiology Volume 240: Number 2 - August 2006 Rowley HA, et al, Contrast-Enhanced MR Imaging of Brain Lesions: A Large-Scale Intraindividual Crossover Comparison of Gadobenate Dimeglumine versus Gadodiamide., AJNR Am J Neuroradiol Jul patients with primary or secondary liver lesions Images evaluated for Confidence in lesion detection Lesion number, character, and diagnosis Enhancement pattern Lesion-to-liver contrast Benefit of dynamic and delayed scans Overall, compared with 0.1 mmol/kg Magnevist, 0.05 mmol/kg MultiHance was Equivalent for dynamic imaging Superior for delayed imaging Schneider G et al. Invest Radiol. 2003;38:85-94

7 MRA MRA 0.1 mmol/kg MultiHance 0.2 mmol/kg Magnevist Clinical Safety Clinical Safety Adverse Events Stability Gadolinium Adverse Events Rare Earth Metal Toxic to Mammals if delivered alone Paramagnetic

8 Adverse Events Contrast Media Adverse Events Rare and most are mild (Idiosyncratic) No difference between any of the agents available in the US today Sites should be prepared to treat a reaction just as they would with iodinated contrast media Then Now Runge VM: Top Magn Reson Imaging 2001 Aug:12(4): Dillman, et. al.: AJR:189 Dec 2007 Murphy, et. al.: AJR:196 Oct 1996 Runge VM: Invest Rad 2001 Vol 36, Num 2, Shellock FG, et. al.: Invest Rad 2006 Vol 41, Num 6, Bleicher, A, Kanal, E AJR: 191, December 2008 Contrast Media Adverse Events Then Happened every day We expected it We were prepared Ammonia capsules Benedryl Epinepherine Atropine O 2 BP cuff IV sets Now Rarely happens We don t expect it We are not prepared Patients not well monitored Drugs locked up Where s the key? Physician available? Just call 911 Andrew Bleicher, Emanuel Kanal AJR: 191, December hospitals and associated imaging centers 13 months and 23,553 doses of MultiHance Data recorded by technologists included dose, related adverse reactions (type and treatment) 13 months and 23,553 doses of MultiHance 178 Reactions (0.76% of CE examinations) 22 Required treatment (13% of reactions) 8 (5%) qualified as serious Stability Bleicher, A, Kanal, E AJR: 191, December 2008

9 Chelate Any of a class of coordination or complex compounds consisting of a central metal atom attached to a large molecule, called a Ligand GBCM Make-up Linear Ionic Linear Non-Ionic Macrocyclic Gd +3 Non-Ionic Ionic Non-Ionic Ionic Linear Non-Ionic Least Stable Agents Ionic Non-Ionic Fundam Clin Pharmacol Dec;20(6): Stability and Transmetalation Concerns regarding stability of chelates are NOT NEW.. Desreux JF, Barthélemy PP Int J Rad Appl Instrum B. 1988;15(1):9-15 Corot C, et al. J Magn Reson Imaging May-Jun;8(3): Puttagunta NR, Gibby WA, Puttagunta VL Invest Radiol Oct;31(10): Gibby WA Invest Radiol Mar;39(3): Laurent S, Elst LV, Muller RN Contrast Media Mol Imaging May;1(3): Idée JM, et al. Fundam Clin Pharmacol Dec;20(6):563-76

10 NSF Nephrogenic Systemic Fibrosis Sadowski, E. A. et al. Radiology 2007;0: Broome DR et al. AJR:188, Feb Nephrogenic Systemic Fibrosis Syndrome: -Skin -Joints -Eyes -Internal Organs ACR: Manual on Contrast Media Version 7, 2010 Nephrogenic Systemic Fibrosis Screening Questions: -Kidney Disease -Acute Kidney Trauma -Sickle Cell -Chemotherapy recently -Liver Transplant -Kidney Transplant Glomerular Filtration Rate Estimation Calculation Based On: -Serum Creatine Level -Age -Sex -Race

11 Glomerular Filtration Rate ACR: Manual on Contrast Media Version 7, 2010 ACR: Manual on Contrast Media Version 7, 2010 ACR: Manual on Contrast Media Version 7, 2010 ACR: Manual on Contrast Media Version 7, 2010

12 Stability Measurements Linear no molecular charge Contrast Agent Thermodynamic Stability Constant (log K eq ) Conditional Stability Constant at ph 7.4 ProHance Magnevist MultiHance Optimark Omniscan Kirchin MA et al. Top Magn Reson Imaging. 2003;14: Summary MR contrast agents are an integral part of MR exams Gadolinium-based agents act by altering relaxation parameters Enhancement based on technique, field strength, dose, concentration and rexlaxivity of the agent Summary Faster imaging techniques require more efficient MR contrast agents Adverse events associated with GBMCAs are rare but occur equally among all agents Thank You! Kristan Harrington, MBA, RT (R) (MR) (ARRT) The risk of NSF in patients with poor renal function again demonstrates differences between agents